8-Aryloctanoic acids of a general formula I having the 2S,4S,5S,7S-configuration,
especially compound such as Aliskiren, wherein R6 represents CH3OCH2CH2CH2O— and R7—NHCH2C(CH3)2CONH2 (IUPAC name: 5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide), are excellent antihypertensive which interfere with the rennin-angiotensin system.
After discovery of the biological activity of the compound of formula I many syntheses, especially for Aliskiren, have been reported (U.S. Pat. No. 5,559,111 and EP 0 678 503). Since Aliskiren contains 4 chiral centers, synthesis of an enantiomerically pure compound is very complex. After 2001 many patents and publications have been published claiming various alternative routes to Aliskiren and the related compounds (WO 01/09083, WO 01/09079, EP 1 215 201, WO 02/02508, WO 02/02500, WO 02/02487, WO 02/08172, WO 02/092828, WO 02/02500, WO 03/103653, UK 2 431 640, GB 2 431 641, GB 2 431 642, GB 2 431 643, GB 2 431 644, GB 2 431 645, GB 2 431 646, GB 2 431 647, GB 2 431 48, GB 2 431 649, GB 2 431 650, GB 2 431 651, GB 2 431 652, GB 2 431 653, GB 2 431 654, WO 2005/054177, WO 2005/090305, WO 2005/051895, WO 2006/131304, WO2006/095020, WO2006/024501, WO2007/054254, WO2007/039183, EP 2 062 874, EP 1958 666, WO 2007/006532, WO2007/045420, WO2008/155338, WO2008/119804, CA 2 634 513, WO2007/048620, WO2007/118681, US2009/0076062, WO2010/010165, EP2189442, WO2009/049837, EP1958666, EP2189442, WO2009/049837, US2009/0076062, WO2011/082506, WO2011/019789, WO2011/064790, WO2010/112482, WO2010/010165, US2011/0092706, US2011/0105767, US2011/0137047, Tetrahedron Letters 2000, 41, 10085, ibid. 2000, 41, 10091, ibid. 2001, 42, 4819, Drugs Fut. 2001, 1139, J. Org. Chem. 2002, 67, 4261, Helv. Chim Acta 2003, 86, 2848, Tetrahedron Letters 2005, 46, 6337, J. Org. Chem. 2006, 71, 4766, Organic Process & Develop 2007, 11, 584, Tetrahedron Letters 2008, 49, 5980 and Org. Lett. 2010, 12, 1816). Nevertheless, none of them in the event fulfills necessary requirements for a cost effective manufacturing process on technical scale.
According to a concept filled in 1994 in the original U.S. Pat. No. 5,559,111, as well as later on in other patents (WO2007/045420), trans-configurated (2S,7S)-2,7-diisopropyloct-4-enedioic acid (or derivatives thereof) has been used as the starting material. C(5)-Amino and C(4)-hydroxy groups attached to this aliphatic C8-chain have been introduced via three step reaction sequence, starting with halo lactonization of trans-double bond followed by displacement of the halogen with an azide and hydrogenation of the azide group. In an alternative approach recently published amino- and hydroxy-groups have been introduced more efficiently starting from cis-configurated (2S,7S)-2,7-diisopropyloct-4-enedioic acid by either direct nitro lactonization or aziridination of cis-double bond (US2011/0137047). Attachment of this chiral C8-aliphatic fragment to the aromatic ring has been always accomplished via addition of an appropriate organometallic reagent, preferably Grignard reagent. The disadvantage of this approach is the use of an expensive trisubstituted aromatic compound such as 4-bromo-2-R6 substituted anisole, which has been prepared from guajacol in 4 steps!, and which is required for the preparation of the organometallic reagent. As sufficiently documented in literature, preparation of organometallic reagents from aryl bromides containing electron-donating groups on the aromatic ring (as e.g. two alkoxy groups) is difficult and requires often special methods resulting in low overall yield. Consequently, synthesis of Aliskiren and related compounds is very expensive because the most expensive aliphatic C8-building block with 4 chiral centers is not used efficiently.
On the other hand, alternative coupling of 2-substituted anisole of formula III with the chiral C8-aliphatic building block of formula IV via Friedel-Crafts reaction has never been reported and such an approach represents a significant advantage against existing syntheses and it is now disclosed in the present invention.